16beta-hydroxymethyl androstanes



it States The present invention relates to certain new cyclopentanoperhydrophenanthrene derivatives and to a method for the preparation thereof.

More particularly, it relates to a method for preparing the novel 16,8-hydroxymethyl derivatives of the androstane series, as well as their esters and ethers, which are represented by the following formulas:

RO- I In the above formulas R represents hydrogen or an acyl radical of 1 to 12 carbon atoms; R represents hydrogen, a lower alkyl group such as methyl, ethyl or propyl, a lower aralkyl group such as benzyl or diphenylmethyl, or an acyl radical derived from a carboxylic acid of up to 12 carbon atoms.

The acyl groups referred to above derive from a carboxylic acid of up to 12 carbon atoms, saturated or unsaturated, of straight, :branched, cyclic or mixed aliphaticcyclic chain, substituted or not with groups such as hydroxyl, methoxy, amino, halogen or other groups; typical such esters are the acetate, propionate, butyrate, valerate, hemisuccinate, enanthate, caproate, be-nzoate, undecenoate, trimethylacetate, phenoxyacetate, cyclopentylpropiohate and fi-chloropropionate.

The compounds object of the present invention are powerful anabolic agents having a favorable anabolicandrogenic ratio, help to increase the protein metabolism and the deposition of calcium on the bone tissue; further- 1 more, they show anti-estrogeni-c activity and inhibit the secretion of gonadotrophins by the pituitary gland.

llhe compounds object of the present invention are obtained by the method illustrated by the following series i (I) H HO R atent O 31188354 Patented May 7, 1963 o 0 l p CHOH I 011203 no HO (11 (In) H H o OR pl onon Tumor:

HO i (v) R0 i an? i H acy o OR IGHiOR CH2OR3 no I no (X): 12:11

I (VI) (XII): R=acv1 11 H l r s e r onion onioa O IX R20 In the above formulas R represents an acyl radical derived from a carboXylic acid of up to 12 carbon atoms; R represents a lower alkyl group or lower aralkyl group.

The starting compound employed for the process object of the present invention is isoandrosterone, which in condensation with ethyl formate in benzene solution and in the presence of sodium hydride or sodium methoxide produces 16-hydroxymethylene-androstan-3B-ol-17-one (II). By catalytic hydrogenation of this compound in the presence of a palladium catalyst, such as 5% palladium on carbon, until the uptake of one molecular equivalent of: hydrogen, there is obtained the lfi-hydroxymethyl compound (III). Adequate solvents for this reaction are tetrahydrofuran, ethyl acetate or lower aliphatic alcohols such as methanol, ethanol, propanol, isopropanol and the like. Conventional esterification of III with hydrocarbon carboxylic acids of up to 12 carbon atoms produce the esters (VII).

By reduction of l6B-hydroxymethyl-androstan-3B-ol- 17-one (III) with a double metal hydride, such as lithium aluminum hydride or sodium borohydride, there is ob- 3 tained 16fi-hydroxymethyl-androstane-3p,17,8-diol (IV), which is esterified with anhydrides or chlorides of carboxylic acids of up to 12 carbon atoms, in pyridine solution, employing conventional methods of esterification, to produce the triesters of l6B-hydroxymethyl-androstane- 35,17B-diol (VIII).

By reacting l6-hydroxymethylene-andronstan-3fl-ol-l7- one (II) with a diazoalkane, such as diazomethane, diazoethane, dimethyldiazomethane or other diazohydrocarbon, such as for example phenyldiazomethane or diphenyldiazomethane, there are obtained the 16-alkoxymethylene or aralkoxymethylene derivatives of androstan-3B-ol-l7- one (V), which upon catalytic hydrogenation in the presence of palladium on carbon, in accordance with the method employed for hydrogenating the l6-hydroxymethylene group to the 16-hydroxymethyl group, gives rise to the formation of the corresponding 165-alkoxymethyl and aralkoxymethyl compound (VI).

By oxidation of the l=6fi-alkoxymethyl and aralkoxymethyl derivatives of androstan-3/3-ol-1-7-one (V1) with 8 N chromic acid in acetone-sulfuric acid solution, or in glacial acetic acid, there are obtained the corresponding 3,1 7diketones (IX).

By reduction of the same compounds (VI) with lithium aluminum hydride or with sodium borohydride, there are obtained the 3,17-diols, i.e., the 16,8-alkoxymethyl and aralkoxymethyl derivatives of androstane-3 5,-17B-diol (X).

The conventional esterifioation of 16B-hydroxymethylandrostane-3 3,l7B-diol (IV), 165-alkoxymethyl and aralkoxymethyl-3/8-ol-l7-one (VI) and l 6i3-alkoxymethyl and aralkoxymethyl-3/3,il75-diol (X) gives rise to the formation of the corresponding esters, i.e. l6l3-acyloxymethyl- 3B,17/3-diacyloxy-androstanes (VIII), 16fl-alkoxymethyl and aralkoxymethyl-3fl-acyloxy androstan-l7 8-one (XI), and 16/3-alkoxy and aralkoxymethyl-3,17B diacyloxyandrostanes (XII).

The following specific examples serve to illustrate but are not intended to limit the present invention:

Example I From a solution of 25 g. of isoandrosterone in 760 .cc. of benzene free of thiophene was distilled 150 cc. of solvent in order to remove moisture by azeotropic distillation. The solution was cooled, treated with 60 cc. of ethyl formate and '18 -g. of sodium methoxide, and the mixture was stirred under an atmosphere of nitrogen for 5 hours; hexane was added until complete precipitation of the sodium salt which was collected by filtration and dried under vacuum. The crude material was suspended in 1 liter of '3 N hydrochloric acid and stirred at room temperature for 2 hours. The precipitate was collected, washed with Water and dried. Recrystallization from methylene chloride-hexane yielded 24 g. of l 6-hydroxymethylene-androstan-3 5-01-17 -one with M.P. 214-215 C., [04] +58 (OHCl )tmax. 266 mp, log E 4.02.

A solution of I10 g. of the latter compound in 1 cc. of tetrahydrofuran was hydrogenated in the presence of 3 g. of palladium on carbon catalyst, at an initial pressure of 33 pounds. After 5 hours, there was added 6 more grams of catalyst and the hydrogenation was continued for 16 hours further. The catalyst was filtered through celite and the filtrate was evaporated to dryness under vacuum. The residue was crystallized from acetone-ether, thus affording 8.4 g. of 1'6fl-hydroxymethylandrostan-3B-ol-l7-one; M.P. 197-199 C., [a] +84 (CHCl A solution of 2 g. of the above hydroxymethyl compound in 20 cc. of anhydrous tetrahydrofuran was added over a period of 30 minutes to a stirred suspension of 2 g. of lithium aluminum hydride in 100 cc. of anhydrous ether. The mixture was stirred at room temperature dior 30 minutes further and the excess of reagent was destroyed with 5 cc. of ethyl acetate and 2 cc. of water. Saturated sodium sulfate solution was added, followed by solid sodium sulfate, and the solution was filtered and the solid was Washed with sufficient hot ethyl acetate. The filtrate was evaporated to dryness and the residue recrystallized from acetone. There was thus obtained 1155 g. of 166- hydroxymethyl-androstane-3 13,17fi-diol; M.P. 266-2 68 C.,

[OCIID +415 Example II To a suspension of 10 g. of 16-hydroxymethyleneandrostan-3B-ol-l17-one in a mixture of 200 cc. of ether and 25 cc. of methanol, there was added an excess of an ether solution of diazomethane; the mixture was kept standing for 10 minutes, the excess of reagent was destroyed by the addition of a few drops of acetic acid and the mixture was evaporated to dryness. The residue was recrystallized from acetone, thus giving 4.19 g. of 1 6- methoxymethylene-androstan-3,6-01-17 one with M.P. 204-206" C., [0:1 i0 (CHCI xmax. 266-267 my, log 4.19.

Example III A solution .of 5.3 g. of l6fi-methoxymethylene-androstan-3fl-ol-l7-one in 50 cc. of anhydrous tetrahydrofuran was hydrogenated in the presence of 1 g. of 5% palladium on carbon at an initial pressure of 32 pounds. After the uptake of 1 mol of hydrogen the catalyst was removed by filtration and the solution evaporated to dryness. Crystallization of the residue from aectone afforded 16pmethoxymethyl-androstan-3fl-ol-17-one with M.P. 207- 209 C., [ab CHCl A solution of 2 1g. of the latter compound in 8 cc. of

Example IV A solution of 1 g. of 1-6fl-methoxymethyl-androstan-3 8- 0l-17-one in cc. of acetone was cooled to 0 C., then treated under an atmosphere of nitrogen and with stirring with an 8 N solution of chromic acid (prepared by mixing 26 g. of chromium trioxide with 23 cc. of concentrated sulfuric acid and diluting with water to 100 cc.), until the color of the reagent persisted in the mixture. The mixture was stirred for -5 minutes further at 0'5 C. and then diluted with water.

The precipitate was collected by filtration, washed with water and dried under vacuum; there was thus obtained a crude product which on crystallization from acetonehexane aiforded 16,8-methoxymethyl-androstane 3,17- dione; M.P. 138-140 C., [a1 +11 (CHCl Example V Example VI A mixture of 1 g. of 16B-hydroxymethyhandrostane- .3fl,l7,8-diol, 5 cc. of pyridine and 5 cc. of acetic anhydride was heated on the steam bath for 2 hours, cooled and the precipitate formed was collected. Crystallization from acetone hexane afforded the triaceta-te of 16f3-hydroxymethyl-androstaneml7/3-diol, which showed a MP. of 130-131 C., [M +11 (CI-101 Example VII By following the method described in Example I, 3 g. of l6fl-methoxymethyl-andr0stan-3,B-o1-17-one was reduced with lithium aluminum :hydride. There was thus obtained 16B-methoxymethyl androstane 35,175 diol which showed M.P. 210-212 C., [(141 +6? (OHCI By esterifying the above compound with acetic anhydride in pyridine in accordance with the method described in the preceding example, there was obtained the diacetate of 16fi-methoxymethyl-androstane-3 3,17/3-diol with M.P. 156-158 C., [ab +8 (OHCI Example VIII A solution of 2 g. of lGfi-hydroxymethyhandrostan-3,8- ol-17-0ne in 8 cc. of pyridine was treated with 4 cc. of benzoyl chloride and then heated on the steam bath for 1 hour. The mixture was poured into ice water and the precipitate formed was collected, washed with water and dried. By recrystallization from methylene chloridehexane, there was obtained the benzoate of 16B benzoyloxymethyl-androstan-3Bo -17-one.

Example IX A mixture of 1 g. of 16,8-hydroxymethyl-androstane- 35,17/3-diol, 5 cc. of pyridine and cc. of cyclopentylpropionic anhydride was kept at room temperature for 18 hours. It was then poured into water and the precipitate formed was collected, thus giving the 3,17-dicyclopentylpropionate of 16,8-cyclopentylpropionoxymethylandrostane-BB, l7B-diol.

Example X To a suspension of 5 g. of 16-hydroxymethylene-androstan-3B-ol-17-one in a mixture of 20 cc. of ether and cc. of methanol, there was added dropwise and under stirring an other solution of diphenyldiazomcthane (Organic Syntheses, Collective Vol. III, p. 351), containing 1.2 molecular equivalents. The mixture was kept standing for 10 minutes, then a few drops of pyridine were added and the solvent was evaporated under reduced pressure. The residue was crystallized from acetone, thus yielding l6-diphenylmethoxymethylene-androstan-3510l- 17-one.

By the same method, but using ether solutions of dimethyl-diazomethane and phenyldiazornethane as alkyl-ating agents, there were respectively obtained 16-isoproxymethylene-androstan-3B-ol 17 one and l6-benzyloxymethylene-androstan-S/FI-ol-17-one.

Example XI Example XII By following the method of esterification described in Example IX, the compounds mentioned below in column I were treated with acid anhydrides in pyridine solution, produce the respective diesters or esters.

I Anhydride H Starting material employed Product obtained lfi-methoxymethylenepropionic propiouate 0f lfi-methoxyandrostan-3fl-ol-17-one. methylene-androstan- 3fl-01-17-one. IGB-methoxymethyldo dipropionate 0f16flandrostan-3B,17B-dlol. ruethoxymethyl-androstane-3B,17fl-diol. lfifi-methoxymethylundecenoicdiundeccnoate M- androstane-3B,17B-di0l. methoxymethyl-androstane-3B,17B-diol. lfifl-isopropoxymethylcaproic caproate of 16B-isopr0- androstan-3fl-0l-17-0ne. poxymethyl-androstan- 3153-0147-0110. lfifl-ethoxymethyl-androacetic acetate of lfifl-ethoxystan-3B-0l-17-one. methyl-androstan-3fl- 01-17-one. lofi-ethoxymethyl-andropropibnicdipropionate of 16pstane-3B,17B-diol. ethoxymcthyl-androstane-3fi,17fl-diol.

I claim: 1. A compound of the following formula:

0 l l GH2O R wherein -R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and R is selected from the group consisting of hydrogen, lower alkyl, lower aralkyl and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

2. 16B-hydroxymethyl-androstan-35-01-17-one.

3. The 16-lower alkyl ethers of 16fi-hydroxymethylandrostan-3B-ol-17-one.

4. 16B-methoxymethyl-androstan-3fl=ol-17-one.

5. The 16-lower analkyl ethers of lfl-hydroxymethylandrostan-3B-ol-17-one.

6. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of the 16-lower alkyl ethers of l6fi-hydroxymethyl-androstan-3p-ol-l7-one.

7. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of the 16-lower aralkyl ethers of 16flhydroxyrnethyl-androstan-3[i-ol-17-one.

8. The acetate of 1ofi-methoxymethyl-androstan-Ilfi-ol- 17-one.

9. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 16fl-hydroxymethyl-androstan-3fi-oll7-one.

10. A compound of the following formula:

15. A compound of the following formula:

wherein R is selected from the group consisting of hydro gen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and R is selected from the group consisting of hydrogen, lower \alkyl, lower aralkyl and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

1 6. 1 6fl-hydroxyrnethybandrostane-3 3, 17 8-dio1.

17. The 16-1ower alkyl ethers of IGB-hydroxymethylandrostan-3fi,17B-diol.

18. The 16-lower aralkyl ethers of l6 8hydroXymethylandrostane-B B, 17 fi-diol.

19. 16fi-methoxymethyl-androstane-3B,1718-diol.

20. The hydrocarbon oarboxylic acid esters of less than 12 carbon atoms of the 16-lower alkyl ethers of 16 3-hydroXymethyl-androstane-B'fi,17/3-diol.

21. The hydrocavbon carboxylic acid esters of less than 12 carbon atoms of the 16-lower aralkyl ethers of 16phydroxymethyl-androstane-3fi, 17 3-dio1.

22. The diacetate of 16,8-methoxymethyl-androstane- 313,17fl-diol.

23. The hydrocarbon carboxylic acid esters of less than 12 carbon atoms of 16,8-hydroXyrnethyl-androstane-3/3, 17/8-dio1.

24. The triace-tate of 16fi-hydroxymethyl-androstane- 36,17B-dio1.

25. 16-lowver alkoxymethylene-androstan-3fl-ol-l7-.one.

26. 16-methoxymethylene-andr0s-tan-3 ,B-o1-17-one.

No references cited. 

1. A COMPOUND OF THE FOLLOWING FORMULA: 